Inhibition of human antigen-specific memory B cell response in vitro by a diphtheria toxin-related interleukin 2 fusion protein

Grailer, Alan P.; Nichols, Jean; Strom, Terry B.; Sollinger, Hans W.; Burlingham, William J.

doi:10.1016/0008-8749(91)90044-c

Cited by 4 publications

(1 citation statement)

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“…Compared to earlier developments by Volkman et al [ 24 ] or Grailer et al . [ 25 ] we established an effective fusion protein expression platform enabling us to produce protein therapeutics in high yields and with homogeneous purity. Using this technology, we were able to show that a peptide fragment of an antigen recognized by the BCR can be used as the cell-binding component of a cytotoxic fusion protein, ensuring that the immunotoxin targets an antigen-specific B cell population without affecting the entire B cell pool.…”

Section: Discussionmentioning

confidence: 99%

Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen

et al. 2016

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BackgroundIn an earlier study we developed a unique strategy allowing us to specifically eliminate antigen-specific murine B cells via their distinct B cell receptors using a new class of fusion proteins. In the present work we elaborated our idea to demonstrate the feasibility of specifically addressing and eliminating human memory B cells.ResultsThe present study reveals efficient adaptation of the general approach to selectively target and eradicate human memory B cells. In order to demonstrate the feasibility we engineered a fusion protein following the principle of recombinant immunotoxins by combining a model antigen (tetanus toxoid fragment C, TTC) for B cell receptor targeting and a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’) to induce apoptosis after cellular uptake. The TTC-ETA’ fusion protein not only selectively bound to a TTC-reactive murine B cell hybridoma cell line in vitro but also to freshly isolated human memory B cells from immunized donors ex vivo. Specific toxicity was confirmed on an antigen-specific population of human CD27+ memory B cells.ConclusionsThis protein engineering strategy can be used as a generalized platform approach for the construction of therapeutic fusion proteins with disease-relevant antigens as B cell receptor-binding domains, offering a promising approach for the specific depletion of autoreactive B-lymphocytes in B cell-driven autoimmune diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12896-016-0249-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen

et al. 2016

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Prolongation of murine thyroid allografts by interleukin 2 (DAB486)-toxin and RS-61443

Hullett

Landry

Eckoff

et al. 1992

Transplant International Official Journal of the European Society for Organ Transplantation

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We evaluated the efficacy of interleukin 2 (DAB486)-toxin (IL-2-diphtheria toxin fusion protein; IL-2-toxin) in combination with RS-61443 to prolong murine thyroid allograft survival. BlO.BR thyroid allografts were transplanted beneath the renal subcapsule in recipient (C57BL/l0 mice and graft survival determined 21 days later. Treatment with IL-2-toxin (25Jlg/day for 14 days) was unable to prolong graft survival significantly. RS-61443 treatment (21 days) achieved significant graft prolongation only at doses of 300 mg/kg daily or greater. When both drugs were used in combination (IL-2-toxin, 25Jlg/day for 14 days RS-61443 200 mg/kg daily for 21 days), statistically significant (P < 0.0001) graft prolongation was obtained. Our results suggest that IL-2-toxin in combination with subtherapeutic RS-61443levels significantly prolongs murine thyroid allograft survival. IL-2toxin and RS-61443, because of their unique and complementary mechanisms, hold promise for more selective immunosuppression.

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Activation of HLA-A2-specific memory B cells in severe combined immunodeficient mice

Niguma¹,

Vito²,

Grailer³

et al. 1993

Human Immunology

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Inhibition of human antigen-specific memory B cell response in vitro by a diphtheria toxin-related interleukin 2 fusion protein

Cited by 4 publications

References 20 publications

Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen

Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen

Prolongation of murine thyroid allografts by interleukin 2 (DAB486)-toxin and RS-61443

Activation of HLA-A2-specific memory B cells in severe combined immunodeficient mice

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